Journal of radiological science and technology (대한방사선기술학회지:방사선기술과학)

Korean Society of Radiological Science (대한방사선과학회)
권호 표지
DOI QR코드

DOI QR Code

Clinical Review of the Current Status and Utility of Targeted Alpha Therapy

표적 알파 치료의 현황 및 유용성에 대한 임상적 고찰

  • Sang-Gyu Choi (Department of Radiation Oncology, Dankook University Hospital)
  • 최상규 (단국대학교병원 방사선종양학과)
  • Received : 2023.09.01
  • Accepted : 2023.09.26
  • Published : 2023.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Targeted Alpha Therapy (TAT) is a new method of cancer treatment that protects normal tissues while selectively killing tumor cells using high cytotoxicity and short range of alpha particles, and target alpha therapy is a highly specific and effective cancer treatment strategy, and its potential has been proven through many clinical and experimental studies. This treatment method accurately delivers alpha particles by selecting specific molecules present in cancer tissue, which has an effective destruction and tumor suppression effect on cancer cells, and one of the main advantages of target alpha treatment is the physical properties of alpha particles. Alpha particles have a very high energy and short effective distance, interacting with target molecules in cancer tissues and having a fatal effect on cancer cells, which is known to cause DNA damage and cell death in cancer cells. TAT has shown positive results in preclinical and clinical studies for various types of cancers, especially those that resist or are unresponsive to existing treatments, but there are several challenges and limitations to overcome for successful clinical transition and application. These include the provision and production of suitable alpha radioisotopes, optimization of target vectors and delivery formulations, understanding and regulation of radiological effects, accurate dosage calculation and toxicity assessment. Future research should focus on developing new or improved isotopes, target vectors, transfer formulations, radiobiological models, combination strategies, imaging techniques, etc. for TAT. In addition, TAT has the potential to improve the quality of life and survival of cancer patients due to the possibility of a new treatment for overcoming cancer, and to this end, prospective research on more carcinomas and more diverse patient groups is needed.

Keywords

Acknowledgement

이 연구는 2022학년도 단국대학교 대학연구비 지원으로 연구되었음.

References

  1. Das T, Pillai MRA. Options to meet the future global demand of radionuclides for radionuclide therapy. Nucl. Med. Biol. 2013;40(1):23-32. DOI: https://doi.org/10.1016/j.nucmedbio.2012.09.007
  2. Yordanova A, Eppard E, KKrpig S, Bundschuh RA, SchKnberger S, Gonzalz-Crmona M, et al. Theranostics in nuclear medicine practice. Onco Targets Ther. 2017; 10:4821-8. DOI: https://doi.org/10.2147/OTT.S140671
  3. Moumaris M, Bretagne JM, Abuaf N. Nanomedical devices and cancer theranostics. Open Nanomedicine J. 2020;6(1):1-11. DOI: https://doi.org/10.2174/2666150002006010001
  4. https://www.iaea.org/newscenter/news/new-technique-to-fight-prostate-cancer-iaea-organizes-first-of-a-kind-training-for-radiopharmacists
  5. Majkowska-Pilip A, Gaweda W, Zelechowska-Matysiak K, Wawrowiczet K, Bilewicz A, et al. Nanoparticles in targeted alpha therapy. Nanomaterials(Basel). 2020;10(7):1-25. DOI: https://doi.org/10.3390/nano10071366
  6. Nedrow JR, Josefsson A, Park S, BKck T, Hobbs RF, Brayton C, et al. Pharmacokinetics, microscale distribution, and dosimetry of alpha-emitter-labeled anti-PD-L1 antibodies in an immune competent transgenic breast cancer model. EJNMMI Res. 2017; 7(1):57. DOI: https://doi.org/10.1186/s13550-017-0303-2
  7. Ackerman NL, Graves EE. The potential for Cerenkov luminescence imaging of alpha-emitting radionuclides. Phys Med Biol. 2012;57(3):771-83. DOI: https://doi.org/10.1088/0031-9155/57/3/771
  8. Seidlin SM, Marinelli LD, Oshry E. Radioactive iodine therapy: Effect on functioning metastases of adenocarcinoma of the thyroid. J Am Med Assoc. 1946;132(14):838-847. DOI: https://doi.org/10.1001/jama.1946.02870490016004
  9. Gudkov SV, Shilyagina NY, Zvyagin AV. Targeted radionuclide therapy of human tumors. Int J Mol Sci. 2015;17(1):1-19. DOI: https://doi.org/10.3390/ijms17010033
  10. https://www.cdc.gov/nceh/radiation/emergencies/glossary.htm#anchor_1556560988
  11. Cherel M, Davodeau F, Kraeber-Bodere F, Chatal JF. Current status and perspectives in alpha radioimmunotherapy, Q. J. Nucl. Med. Mol. Imaging 2006; 50:322-9. Retrieved from https://pubmed.ncbi.nlm.nih.gov/17043629/
  12. Sgorous G. Alpha-particles for targeted therapy. Adv Drug Deliv Rev. 2008;60(12):1402-6. DOI: https://doi.org/10.1016/j.addr.2008.04.007
  13. Harrison MR, Wong TZ, Armstrong AJ, George DJ. Radium-223 chloride: A potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Manag. Res. 2013;5:1-14. DOI: https://doi.org/10.2147/CMAR.S25537
  14. Walicka MA, Vaidyanathan G, Zalutsky MR, Adelstein SJ, Kassis AI. Survival and DNA damage in chinese hamster V79 cells exposed to alpha particles emitted by DNA-incorporated astatine-211. Radiat. Res. 1998;150(3):263-8. DOI: https://doi.org/10.2307/3579974
  15. Sgouros G, Song H. Cancer stem cell targeting using the alpha-particle emitter, 213 Bi: Mathematical modeling and feasibility analysis George. Cancer Biother. Radiopharm. 2008;23(1):74-81. DOI: https://doi.org/10.1089/cbr.2007.0408
  16. Poty S, Francesconi LC, McDevitt MR, Morris MJ, Lewis JS. α-Emitters for radiotherapy: From basic radiochemistry to clinical studies-Part 2. J. Nucl. Med. 2018;59(7):1020-7. DOI: https://doi.org/10.2967/jnumed.117.204651
  17. Sollini M, Marzo K, Chiti A, Kirienko M. The five "W"s and "How" of targeted alpha therapy: Why? Who? What? Where? When? and How? Rend. Fis. Acc. Lincei. 2020;31:231-47. DOI: https://doi.org/10.1007/s12210-020-00900-2
  18. Huang CY, Oborn BM, Guatelli S, Allen BJ. Monte Carlo calculation of the maximum therapeutic gain of tumor antivascular alpha therapy. Med. Phys. 2012;39(3):1282-8. DOI: https://doi.org/10.1118/1.3681010
  19. Kassis AI. Therapeutic radionuclides: Biophysical and radiobiologic principles. Semin. Nucl. Med. 2008;38(5):358-66. DOI: https://doi.org/10.1053/j.semnuclmed.2008.05.002
  20. Tasnim I, Tala HS. Range of alpha particles in human tissue. J of Engineering and Applied Science. 2019;14(15):5060-3. DOI: https://doi.org/10.36478/jeasci.2019.5060.5063
  21. Pouget JP, Mather SJ. General aspects of the cellular response to low- and high-LET radiation. Eur. J. Nucl. Med. 2001;28(4):541-61. DOI: https://doi.org/10.1007/s002590100484
  22. Song H, Senthamizhchelvan S, Hobbs RF, Sgouros G. Alpha particle emitter radiolabeled antibody for metastatic cancer: What can we learn from heavy ion beam radiobiology? Antibodies. 2012;1(2):124-48. DOI: https://doi.org/10.3390/antib1020124
  23. Elbakry A, LKbrich M. Homologous recombination subpathways: A tangle to resolve. Sec. Human and Medical Genomics. Mini Review. 2021;12:1-7. DOI: https://doi.org/10.3389/fgene.2021.723847
  24. Li X, Heyer WD. Homologous recombination in DNA repair and DNA damage tolerance. Cell Research. 2008;18(1):99-113. DOI: https://doi.org/10.1038/cr.2008.1
  25. Hamada N, Maeda M, Otsuka K, Tomita M. Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects. Curr Mol Pharmacol. 2011;4(2):79-95. DOI: https://doi.org/10.2174/1874467211104020079
  26. Azzam EI, De Toledo SM, Little JB. Oxidative metabolism, gap junctions and the ionizing radiation-induced bystander effect. Oncogene. 2003; 22(45):7050-7. DOI: https://doi.org/10.1038/sj.onc.1206961
  27. Azzam EI, De Toledo SM, Gooding T, Little JB. Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low uences of alpha particles. Radiat Res. 1998;150:497-504. DOI: https://doi.org/10.2307/3579865
  28. Wu LJ, Randers-Pehrson G, Xu A, Waldren CA, Geard CR, Yu Z, et al. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc Natl Acad Sci USA. 1999; 96(9):4959-64. DOI: https://doi.org/10.1073/pnas.96.9.4959
  29. Azzam EI, De Toledo SM, Spitz DR, Little JB. Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures. Cancer Res. 2002;62(19):5436-42. Retrieved from https://aacrjournals.org/cancerres/article/62/19/5436/509200/Oxidative-Metabolism-Modulates-Signal-Transduction
  30. Matsumoto H, Hayashi S, Hatashita M, Ohnishi K, Shioura H, Ohtsubo T, et al. Induction of radioresistance by a nitric oxide-mediated bystander effect. Radiat Res. 2001;155(3):387-96. https://doi.org/10.1667/0033-7587(2001)155[0387:IORBAN]2.0.CO;2
  31. Prise KM, O'Sullivan JM. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer. 2009;9(5):351-60. DOI: https://doi.org/10.1667/0033-7587(2001)155[0387:iorban]2.0.co;2
  32. Sgouros G, Bodei L, Mcdevitt MR, Nedrow JR. Radiopharmaceutical therapy in cancer: Clinical advances and challenges. Nat Rev Drug Discov. 2020;19:589-608. DOI: https://doi.org/10.1038/s41573-020-0073-9
  33. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-35. DOI: https://doi.org/10.1056/NEJMoa1607427
  34. Pallares RM, Abergel RJ. Transforming lanthanide and actinide chemistry with nanoparticles. Nanoscale. 2020;12:1339-48. DOI: https://doi.org/10.1039/C9NR09175K
  35. Yue J, Pallares RM, Cole LE, Coughlin EE, Mirkin CA, Lee A, et al. Smaller CpG-conjugated gold nanoconstructs achieve higher targeting specificity of immune activation. ACS Appl Mater Interfaces. 2018;10(26):21920-6. DOI: https://doi.org/10.1021/acsami.8b06633
  36. Pallares RM, Choo P, Cole LE, Mirkin CA, Lee A, Odom TW. Manipulating immune activation of macrophages by tuning the oligonucleotide composition of gold nanoparticles. Bioconjug Chem. 2019;30(7):2032-7. DOI: https://doi.org/10.1021/acs.bioconjchem.9b00316
  37. Xie D, Wang MP, Qi WH. A simplified model to calculate the surface-to-volume atomic ratio dependent cohesive energy of nanocrystals. J Phys Condensed Matter. 2004;16(36):401-5. DOI: https://doi.org/10.1088/0953-8984/16/36/L01
  38. Piotrowska A, Meczynska-Wielgosz S, Majkowska-Pilip A, Kozminski P, WKjciuk G, CKdrowska E, et al. Nanozeolite bioconjugates labeled with 223Ra for targeted alpha therapy. Nucl Med Biol. 2017;47:10-8. DOI: https://doi.org/10.1016/j.nucmedbio.2016.11.005
  39. Sattiraju A, Xiong X, Pandya D, Wadas T, Xiong X, Sun Y, et al. Alpha particle enhanced blood brain/tumor barrier permeabilization in glioblastomas using integrin alpha-v beta-3-targeted liposomes. Mol Cancer Ther. 2017;16(10):2191-200. DOI: https://doi.org/10.1158/1535-7163.MCT-16-0907
  40. Mckeage K, Perry CM. Trastuzumab: A review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs. 2002;62(1):209-43. DOI: https://doi.org/10.2165/00003495-200262010-00008
  41. Caron PC, Jurcic JG, Scott AM, Finn RD, Divgi CR, Graham MC, et al. A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: Specific targeting without immunogenicity. Blood. 1994;83(7):1760-8. DOI: https://doi.org/10.1182/blood.V83.7.1760.1760
  42. Simmons D, Seed B. Isolation of a cDNA encoding CD33, a differentiation antigen of myeloid progenitor cells. J Immunol. 1988;141(8):2797-800. DOI: https://doi.org/10.4049/jimmunol.141.8.2797
  43. Chang SS. Overview of prostate-specific membrane antigen. Rev Urol. 2004;6:S13-8. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472940/
  44. Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57(12):1941-1944. DOI: https://doi.org/10.2967/jnumed.116.178673
  45. Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, et al. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: A pilot study. Eur J Nucl Med Mol Imaging. 2019;46(1):129-138. DOI: https://doi.org/10.1007/s00259-018-4167-0
  46. Couturier O, Supiot S, Degraef-Mougin M, Faivre-Chauvet A, Carlier T, Chatal JF, et al. Cancer radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med Mol Imaging. 2005;32(5): 601-14. DOI: https://doi.org/10.1007/s00259-005-1803-2
  47. Scheinberg DA, McDevit MR. Actinium-225 in targeted alpha-particle therapeutic applications. Curr Radiopharm. 2011;4(4):306-20. DOI: https://doi.org/10.2174/1874471011104040306
  48. Wadas TJ, Pandya DN, Solingapuram Sai KK, Mintz A. Molecular targeted α-particle therapy for oncologic applications. Am J Roentgenol. 2014;203(2): 253-60. DOI: https://doi.org/10.2214/AJR.14.12554
  49. McDevitt MR, Finn RD, Ma D, Larson SM, Scheinbeerg DA. Preparation of alpha-emitting 213Bi-labeled antibody constructs for clinical use. J Nucl Med. 1999;40(10):1722-7. Retrieved from https://pubmed.ncbi.nlm.nih.gov/10520715/ 10520715
  50. Larsen RH, Wieland BW, Zalutsky MR. Evaluation of an internal cyclotron target for the production of 211At via the 209Bi (α,2n)211 at reaction. Appl. Radiat. Isot. 1996;47(2):135-43. DOI: https://doi.org/10.1016/0969-8043(95)00285-5
  51. Nilsson S, Larsen RH, Fossa SD, Balteskard L, Borch KW, Westlin JE, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin. Cancer Res. 2005;11(12):4451-9. DOI: https://doi.org/10.1158/1078-0432.CCR-04-2244
  52. Larsen RH, Borrebaek J, Dahle J, Melhus KB, Krogh C, Valan MH, et al. Preparation of 227Th-labeled radioimmunoconjugates, assessment of serum stability and antigen binding ability. Cancer Biother. Radiopharm. 2007;22:431-37. DOI: https://doi.org/10.1089/cbr.2006.321
  53. Kozak RW, Atcher RW, Gansow OA, Friedman AM, Hines JJ, Waldmann TA. Bismuth-212-labeled anti-tac monoclonal antibody: alpha-particle-emitting radionuclides as modalities for radioimmunotherapy. Proc. Natl. Acad. Sci. USA. 1986;83(2):474-8. DOI: https://doi.org/10.1073/pnas.83.2.474
  54. Parker C, Heinrich D, O'Sullivan JM, Fossa S. Overall survival benefit of Radium223 Chloride (AlpharadinTM) in the treatment of patients with symptomatic bone metastases in Castration-resistant Prostate Cancer (CRPC): A phase III randomized trial (ALSYMPCA). 2011 European Journal of Cancer. 2011;47(2):3-3. Retrieved from https://abstracts.ncri.org.uk/abstract/overall-survival-benefit-of-radium-223-chloride-alpharadin-in-the-treatment-of-patients-with-symptomatic-bone-metastases-in-castration-resistant-prostate-cancer-crpc-a-phase-iii-randomiz-3/ https://doi.org/10.1016/S0959-8049(11)70100-9
  55. Tagawa ST, Sun M, Sartor AO, Thomas C, Singh S, Bissassar M, et al. Phase I study of 225Ac-J591 for men with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 2021;39(15): 5015. DOI: https://doi.org/10.1200/JCO.2021.39.15_suppl.5015
  56. Tagawa ST, Sun MP, Nauseef JT, Thomas C, Castellanos SH, Thomas JE, et al. Phase I dose-escalation results of prostate-specific membrane antigen-targeted radionuclide therapy (PSMA-TRT) with alpha-radiolabeled antibody 225Ac-J591 and beta-radioligand 177Lu-PSMA I&T. J. Clin. Oncol. 2023;41:5018. DOI: https://doi.org/10.3390/ijms241411626
  57. Jurcic GJ, Larson SM, Sgouros G, Mcdevitt MR, Finn RD, Divgi CR, et al. Targeted αparticle immunotherapy for myeloid leukemia. Blood. 2002; 100(4):1233-9. DOI: https://doi.org/10.1182/blood.V100.4.1233.h81602001233_1233_1239
  58. Rosenblat TL, McDevitt MR, Mulford DA, Pandit-Tskar N, Divgi CR, et al. Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia. Clin Cancer Res. 2010;16(21):5303-11. DOI: https://doi.org/10.1158/1078-0432.CCR10-0382
  59. https://www.doctorsnews.co.kr/news/articleView.html?idxno=21794
  60. Schmidt DF, Neumann C, Antke C, Apostolidis S, Martin A, Morgenstern R, et al. Phase 1 clinical study on alpha-therapy for non-Hodgkin lymphoma. In 4th Alpha-Immunotherapy Symposium, A Morgenstern, Ed. Dusseldorf, Germany; 2004.
  61. Kwekkeboom DJ, De Herder WW, Kam BL, Van Eijck CH, Van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3] octreotate: Toxicity, efficacy, and survival. J. Clin. Oncol. 2008;26(13):2124-30. DOI: https://doi.org/10.1200/JCO.2007.15.2553
  62. Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, et al. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: A first-in-human experience. Eur. J. Nucl. Med. Mol. Imaging. 2014;41(11):2106-19. DOI: https://doi.org/10.1007/s00259-014-2857-9
  63. http://www.bosa.co.kr/news/articleView.html?idxno=2201031
  64. Krolicki L, Bruchertseifer F, Kunikowska J, Koziara H, Krolicki B, Jakucinski M, et al. Safety and efficacy of targeted alpha therapy with 213Bi-DOTAsubstance P in recurrent glioblastoma. Eur J Nucl Med Mol Imaging. 2019;46(3):614-22. DOI: https://doi.org/10.1007/s00259-018-4225-7
  65. Cordier D, Forrer F, Bruchertseifer F, Morgenstern A, Apostolidis C, Good S, et al. Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA-[Thi8,Met(O2)11]-substance P: A pilot trial. Eur J Nucl Med Mol Imaging. 2010;37(7):1335-44. DOI: https://doi.org/10.1007/s00259-010-1385-5
  66. Zalutsky MR, Reardon DA, Akabani G, Coleman RE, Friedmn AH, Friedmn HS, et al. Clinical experience with alpha-particle emitting 211At: Treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6. J Nucl Med. 2008;49(1):30-8. DOI: https://doi.org/10.2967/jnumed.107.046938
  67. Andersson H, Cederkrantz E, Back T, Divgi C, Elgqvist J, Himmelman J, et al. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: Pharmacokinetics and dosimetry of (211)At-MX35 F(ab')2-A phase I study. J. Nucl. Med. 2009;50(7):1153-60. DOI: https://doi.org/10.2967/jnumed.109.062604
  68. Pallares RM, Abergel RJ. Development of radiopharmaceuticals for targeted alpha therapy: Where do we stand? Front. Med. 2022:1-16. DOI: https://doi.org/10.3389/fmed.2022.1020188
  69. Allen BJ, Raja C, Rizvi S, Li Y, Tsui W, Zhang D, Song E, et al. Targeted alpha therapy for cancer. Phys Med Biol. 2004;49(16):3703-12. DOI: https://doi.org/10.1088/0031-9155/49/16/016
  70. McDevitt MR, Sgouros G, Finn RD, Humm JL, Jurcic JG, Larson SM, et al. Radioimmunotherapy with alpha-emitting nuclides. Eur J Nucl Med. 1998;25(9):1341-51. DOI: https://doi.org/10.1007/s002590050306
  71. Cordes N, Meineke V. Cell adhesion-mediated radioresistance (CAM-RR): Extracellular matrix-dependent improvement of cell survival in human tumor and normal cells in vitro. Strahlenther Onkol. 2003;179(5):337-44. DOI: https://doi.org/10.1007/s00066-003-1074-4
  72. Radchenko V, Morgensten A, Jalilian AR, Ramogida CF, Cutler C, Duchemin C, et al. Production and supply of alpha particles emitting radionuclides for Targeted Alpha Therapy (TAT). J Nucl Med. 2021; 62(11):1495-503. DOI: https://doi.org/10.2967/jnumed.120.261016
  73. Pouget JP, Constanzo J. Revisiting the radiobiology of targeted alpha therapy. Front Med. 2021;8:1-11. DOI: https://doi.org/10.3389/fmed.2021.692436
  74. Kim YS, Brechbiel MW. An overview of targeted alpha therapy. Tumor Biol. 2012;33(3):573-90. DOI: https://doi.org/10.1007/s13277-011-0286-y
  75. Morgenstern A, Apostolidis C, Kratochwil C, Sathekge M, Krolicki L, Bruchertseifer F. An overview of targeted alpha therapy with actinium-225 and bismuth-213. Curr Radiopharm. 2018;11(3):200-208. DOI: https://doi.org/10.2174/1874471011666180502104540
  76. Choi SG. Literature review of clinical usefulness of heavy ion particle as an new advanced cancer therapy. Journal of Radiological Science and Technology. 2019;42(6):413-22. DOI: http://dx.doi.org/10.17946/JRST.2019.42.6.413
  77. Song GS, Bae JR, Kim JG. A comparison for treatment planning of tomotherapy and proton therapy in prostate cancer. Journal of Radiological Science and Technology. 2013;36(1):31-8. DOI: https://doi.org/10.17946/JRST.2019.42.6.413